The human hemoglobin molecule consists of a protein heterotetramer (two α-like globin chains and two β-like globin chains) and four non-protein heme groups. The α-like and β-like globin gene clusters are located on different chromosomes, and expression of the different globin genes within the two gene clusters are under temporal control during development. Genetic defects, such as deletions or mutations, inside these globin gene loci result in abnormal synthesis of hemoglobins and consequently lead to hemoglobinopathies.
β-thalassemia and sickle cell disease are the two most common hemoglobinopathies, which together affect approximately 4.5% of populations worldwide. β-thalassemia is the result of either a deletion or mutation within the β-like globin gene cluster, diminishing the synthesis of adult β globin chain. Severe deficiency or absence of the β globin chain leads to imbalanced expression of the adult a globin chain and the overloaded α globin chain in turn precipitates and damages the red cell membrane, ultimately inducing rapid apoptosis of the erythrocytes during early erythroblast development (also termed β-thalassemia major or Cooley's anemia). Individuals with β-thalassemia major become profoundly anemic within 6 to 9 months after birth, the time when the hemoglobin switch is completed from HbF (α2/β2) to HbA (α2/β2).
Sickle cell disease is caused by a point mutation at the sixth position of the β globin chain (from Glu to Val). Patients with sickle cell disease are characterized by the existence of sickle hemoglobin HbS (α2/β3S2). The mutated adult β globin chain promotes the polymerization of HbS at low oxygen condition, which distorts the red blood cells into the characteristic sickle shape. The illness of sickle cell disease is primarily caused by hemolysis, since the misshaped sickle cells are destroyed inside the spleen within 10-20 days. With high risk of early death, life expectancy of patients with the sickle cell disease is reported to be shortened to an average of 42-48 years. Impairing the generation of normal adult hemoglobin, both β-thalassemia major and sickle cell disease patients require regular blood transfusion to replenish functional HbA for survival. However, constant transfusions are accompanied by a high cost (exceeding 1 billion US dollars per year in the US alone) and a high risk of iron overloading which often leads to death.
In both β-thalassemia and sickle cell disease, the elevated expression of HbF has been reported to be helpful in improving the clinical symptoms of the underlying diseases. In β-thalassemia major patients, elevation of the fetal γ globin chain synthesis balances the excess a globin chains by formation of HbF, thus modulating the severe anemia in patients. Moreover, the increase of the γ globin chain can also prevent the formation of HbS, and the existence of HbF directly inhibits the polymerization of HbS in the sickle cell patients.
Thus, pharmacological induction of HbF in patients with hemoglobinopathies is a potentially useful therapeutic strategy. To date, several chemotherapeutic agents, such as trichostatin A (histone deacetylase inhibitor), apicidin (histone deacetylase inhibitor), 5′-aza-cytidine (DNA methyltransferase inhibitor), hydroxyurea (ribonucleotide reductase inhibitor), butyrate and other short-chain fatty acids, have been demonstrated to stimulate fetal hemoglobin production. However, most of these HbF inducers show variable efficacies from individual to individual, low specificity in globin gene induction, and high toxicity with irreversible apoptosis. Among these drugs, hydroxyurea is the first US FDA-approved medicine for the curing of hemoglobinopathies disease. Unfortunately, approximately 25% of the recipients are poor or non-responders to hydroxyurea treatment. Moreover, potential side effects of myelosuppression and reproductive toxicity exist, leading to therapeutic concerns for the usage of hydroxyurea in patients.
In view of this, compounds that induce expression of endogenous embryonic/fetal globin chains for the treatment of β-thalassemia major and sickle cell diseases are of great clinical interest.